Benzazine derivatives as phosphodiesterase 4 inhibitors

ABSTRACT

Compounds of formula I:                    
     wherein A is a heterocycle containing a nitrogen atom and optionally saturated or unsaturated and optionally further substituted by an oxo group (═O); R is: hydrogen, cyano, (C 1-4 )alkoxycarbonyl, carbamoyl; optionally substituted (C 4-7 )-cycloalkyl, aryl or heterocycle; (C 1-8 )alkyl, (C 2-8 )alkenyl or (C 2-8 )alkynyl optionally branched and/or substituted by (C 4-7 ) cycloalkyl, aryl or heterocycle; aryloxy, heterocyclyloxy, aryl(C 1-4 )alkoxy, heterocyclyl(C 1-4 )alkoxy, amino substituted by one or two (C 1-4 )alkyl group(s), aryl-amino, heterocyclyl-amino, aryl(C 1-4 )alkyl-amino, or heterocyclyl(C 1-4 )alkylamino; Y is methylene or ethylene; W is an optionally substituted aryl or heterocycle; R 1  is hydrogen, (C 4-7 )cycloalkyl or a (C 2-8 )alkyl, (C 2-8 )alkenyl or (C 2-8 )alkynyl group optionally substituted by hydroxy, oxo, (C 4-7 )cycloalkyl, aryl or heterocycle, and optionally interrupted by one or more heteroatom(s) or heterogroup(s); R 2  is a (C 1-6 )alkyl or polyfluoro(C 1-6 )alkyl group; the N→O derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof. The compounds of formula (I) are PDE 4 inhibitors and may be used in compositions and methods involving PDE 4 inhibition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national-stage filing under 371 of PCT/EP99/07302,filed Oct. 10, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to benzazine derivatives, to thepharmaceutical compositions containing them and to their use asphosphodiesterase 4 inhibitors.

2. Description of Related Art

Phosphodiesterases are a family of isoenzymes which constitute the basisof the main mechanism of cAMP (cyclic adenosine-3′,5′-monophosphate)hydrolytic inactivation. cAMP has been shown to be the second messengermediating the biologic response to many of hormones, neurotransmittersand drugs (Krebs Endocrinology Proceedings of the 4th InternationalCongress Excerpta Medica, 17-29, 1973). When the suitable agonist bindsto the cell surface, the adenylated cyclase activates and turns Mg²⁺-ATPinto cAMP. cAMP modulates the activity of the majority, if not of allthe cells contributing to the pathophysiology of various respiratorydiseases, both of allergic origin and not. It follows that an increaseof the cAMP concentration yields beneficial effects such as airwaysmooth muscle relaxation, inhibition of the mast cell mediator release(basophil granulose cells), suppression of the neutrophil and basophildegranulation, inhibition of the monocyte and macrophage activation.Thus, compounds able of activating adenylate cyclase or of inhibitingphosphodiesterases could suppress the undesired activation of the airwaysmooth muscle and of a great number of inflammatory cells.

In the phosphodiesterase family there is a distinct group of isoenzymes,phosphodiesterases 4 (hereinafter PDE 4) specific for the hydrolysiscAMP in the airway smooth muscle and inflammatory cells (Torphy,“Phosphodiesterase Isoenzymes: Potential Targets for NovelAnti-asthmatic Agents” in New Drugs for Asthma, Barnes, ed. IBCTechnical Services Ltd, 1989). Studies carried out on this enzyme showthat its inhibition yields not only the airway smooth muscle relaxation,but also the suppression of mastocyte, basophil and neutrophildegranulation, so as the inhibition of the monocyte and neutrophilactivation. In addition, the action of PDE 4 inhibitors is markedlystrengthened when the adenylate cyclase activity of the target cells isincreased by endogenous hormones, as it happens in vivo. Thus PDE 4inhibitors are effective in the therapy of asthma. Such compounds offera unique approach to the therapy of various respiratory diseases, bothof allergic origin and not, and possess significant therapeuticadvantages over the current therapy.

The excessive or irregular production of tumour necrosis factor(hereinafter TNF_(α)), a cytokine with pro-inflammatory activityproduced by various kinds of cells, affects the mediation or theexacerbation of many pathologies such as, for example, the adultrespiratory distress syndrome (ARDS) and the chronic pulmonaryinflammatory disease. Therefore compounds able to control the negativeeffects of TNF_(α), i.e. the inhibitors of this cytokine, are to beconsidered as useful against many pathologies.

The patent application EP 0 490 823 (Sandoz) illustrates isoquinolinesof formula

wherein

R₁-R₄ are lower alkoxy groups, as inhibitors of phosphodiesterase III,IV and V.

The patent application EP 0 491 441 (Shell Internationale Research)describes, inter alia, isoquinolines of formula

wherein R₁-R₄ are hydrogen, alkyl or alkoxy; R₅ and R₆ are hydrogen ortogether form a bond; R₇ is hydrogen, alkyl or alkoxy; R₈ and R₉ arehydrogen or together form a bond; and A is an optionally substitutedphenyl. These compounds have fungicide activity in agricultural field.

The patent GB 1,199,768 (Pfizer) describes, inter alia, compounds offormula

wherein A and B are independently hydrogen or (C₁₋₅)alkoxy; R₁ ishydrogen, an optionally substituted alkyl, benzyl, phenyl or phenethylgroup, D₁ and D₂ are alternatively —N═ or —CH═; and Y is —NR₆R₇ whereinR₆ and R₇ are independently hydrogen or an aryl up to 10 carbon atomsoptionally substituted by 1-3 halogen atoms. These compounds arebronchodilators and anti-hypertensives.

The U.S. Pat. No. 5,556,862 (Nippon Zoki Pharmaceutical) claimspharmaceutical compositions containing isoquinolines of formula

wherein R is hydrogen or alkoxy, useful as PDE 4 inhibitors.

The patent application WO 97/04779 (Chirosciente) claims, inter alia,quinolinones of formula

wherein R₁ is (C₁₋₆)alkyl or (C₁₋₆)alkyl-heterocycle optionallysubstituted by halogen atoms; R₃ is phenyl or pyridyl, furyl, etc.:R₄-R₇ are hydrogen or (C₁₋₆)alkoxy, and n is 0-3. These compounds arePDE 4 and TNF_(α) inhibitors.

The patent application EP 0 569 592 (Otsuka) describes quinolinones offormula

wherein R represents several kinds of chains ending with an amino group;A is lower alkylene and W is O or S. These compounds arephosphodiesterase inhibitors in general with particular reference to aninhibiting activity of piastrinic aggregation.

The patent application WO 97/38977 (Astra) claims isoquinolines offormula

wherein R can be alkyl or a cyclic substituent, R₁ can be hydrogen orphenylalkyl, R₂ can be hydrogen, alkyl or phenyl-alkynyl and R₃ ishydrogen or a halogen atom. These compounds have anti-inflammatoryactivity.

The patent application EP 0 848 000 (Tanabe Seiyaku) describes compoundsof formula

wherein A is one of the rings

wherein R₁ and R₂ are hydrogen or an optionally protected hydroxy group;R₃₁, R₄₁, and R₄₂ are optionally protected hydroxymethyl; R₃₂ ishydrogen, lower alkyl or optionally protected hydroxymethyl; and R₅ andR₆ are hydrogen, amino or can form a heterocycle. These compounds arePDE 4 inhibitors.

It has been now surprisingly found a new class of benzazine derivativesable to selectively inhibit PDE 4 and further to inhibit TNF_(α).

DETAILED DESCRIPTION OF THE INVENTION

Therefore the present invention relates to compounds of formula

wherein

A is a heterocycle containing a nitrogen atom and optionally unsaturatedand optionally further substituted by an oxo group (═O);

R is hydrogen, cyano, (C₁₋₄)alkoxycarbonyl, carbamoyl; optionallysubstituted (C₄₋₇)-cycloalkyl, aryl or heterocycle; (C₁₋₈)alkyl,(C₂₋₈)alkenyl or (C₂₋₈)alkynyl optionally branched and/or substituted by(C₄₋₇)cycloalkyl, aryl or heterocycle; aryloxy, heterocyclyloxy,aryl-(C₁₋₄)alkoxy, heterocyclyl(C₁₋₄)alkoxy, amino substituted by one ortwo (C₁₋₄)alkyl group(s), aryl-amino, heterocyclyl-amino,aryl(C₁₋₄)alkyl-amino heterocyclyl(C₁₋₄)alkylamino;

Y is methylene or ethylene;

W is an optionally substituted aryl or heterocycle:

R₁ is hydrogen, (C₄₋₇)cycloalkyl or a (C₁₋₈)alkyl, (C₂₋₈)alkenyl or(C₂₋₈)alkynyl group optionally substituted by hydroxy, oxo,(C₄₋₇)cycloalkyl, aryl or heterocycle, and optionally interrupted by oneor more heteroatom(s) or heterogroup(s);

R₂ is a (C₁₋₆)alkyl or polyfluoro(C₁₋₆)alkyl group;

the N→O derivatives of the compounds of formula I and thepharmaceutically acceptable salts thereof.

The compounds of formula I can have an asymmetric centre and thus be inform of stereoisomers. Object of the present invention are compounds offormula I in form of stereoisomeric mixtures so as of singlestereoisomers.

Preferred compounds according to the invention are those of formula Iwherein R is hydrogen, (C₄₋₇)cycloalkyl, aryl, (C₁₋₈)alkyl optionallybranched and/or substituted by (C₄₋₇)-cycloalkyl or aryl; R₁ ishydrogen, (C₄₋₇)cycloalkyl or a (C₁₋₈)alkyl optionally substituted by(C₄₋₇)cycloalkyl, aryl or heterocycle, and optionally interrupted by oneor more heteroatoms or heterogroups; and W is an optionally substitutedheterocycle.

Still more preferred compounds according to the invention are those offormula I wherein R is hydrogen, (C₄₋₇)cycloalkyl, aryl, (C₁₋₈)alkyloptionally branched and/or substituted by (C₄₋₇)cycloalkyl or aryl; R₁is hydrogen and W is a substituted pyridine.

The compounds of formula I are active as selective PDE 4 and TNF_(α)inhibitors and thus are used as therapeutic agents in allergic andinflammatory pathologies such as, for example, emphysema, chronicbronchitis, asthma and allergic rhinitis.

As heterocycle it is meant an optionally partially or totallyhydrogenated aromatic ring containing one or more heteroatom(s) selectedamong oxygen, nitrogen and sulfur, for example pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine,triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline,pyrazolidine, imidazolidine, piperidine, furan, pyran, isothiazole,isoxazole, thiophene and the like.

Specific example of alkyl groups are methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, 1-methyl-butyl, 2-ethyl-propyl,3-methyl-butyl, 3-methyl-2-butyl, n-hexyl, heptyl, octyl and the like.As (C₄₋₇)cycloalkyl group cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl are meant, and when it contains an oxygen atom,tetrahydrofuran or tetrahydropyran, for example, are meant, while arylmeans an aromatic C₆₋₁₀ ring or system such as, for example, phenyl,naphthyl, indanyl, and the like.

Specific examples of substituents present on the W ring are halogens,such as chlorine, bromine, fluorine and iodine, (C₁₋₄)alkyl, hydroxy,nitro and carboxy.

The N→O group optionally present in the compounds of formula I can beboth on the nitrogen of the benzazine ring and on those optionallypresent on the W substituent.

Pharmaceutically acceptable salts of the compounds of formula I arethose with organic and inorganic acids, such as, for example,hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric,acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, aspartic,methanesulfonic and 3,7-di-t.butylnaphthalen-1,5-disulfonic (dibudinicacid).

The preparation of the compounds of formula I proceeds according tomethods for the synthesis of benzazine derivatives known to the skilledin the art (see, for example Chemistry of Heterocyclic Compounds, NY,London). Herein after the synthesis of some compounds of formula I isillustrated in more details while for others reference is made to thespecific examples.

For example, when compounds of formula I being 3,4-dihydro-isoquinolinesare to be obtained, the synthesis starts from a compound of formula

wherein R, R₁, R₂ are as defined above, which is reacted with a compoundof formula

W—Y—Z  (III)

wherein W and Y are as defined above, and Z is a carboxy group or areactive derivative thereof such as, for example, the acyl chloride.When Z is a carboxy group the reaction occurs in the presence ofactivating agents such as, for example, 1-hydroxybenzotriazole (HOBT),dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole. Thus it isobtained a compound of formula

wherein R₁, R₂, R, W and Y are as defined above, which is cyclised, forexample, in the presence of phosphoryl chloride. The result of thiscyclisation depends on the position of R₁ and —OR₂ and can bring to oneor more isomer(s) which are separated, for example, by chromatographictechniques or by crystallisation.

The intermediate of formula II can be obtained starting from an aldehydeof formula

wherein R₂ is as defined above, whose hydroxy function is activated, forexample with triflic anhydride, to give a compound of formula

wherein R₂ is as defined above, and T is an activating group. Thiscompound undergoes a coupling reaction in the presence of a catalyst,for example palladium, to give an aldheyde of formula

wherein R₁ and R₂ are as defined above. This is reacted withnitromethane to give a compound of formula

wherein R₁ and R₂ are as defined above, which is reduced, for examplewith lithium aluminium hydride, to give the intermediate of formula II(R═H).

The compound of formula II (R≠H) is obtained by reacting the compoundVIII with the suitable metalloorganic for example a Grignard reactive,to give a compound of formula

wherein R₁ and R₂ are as defined above and R is different from H, whichby reduction, for example with Pd/C, gives the correspondingintermediate of formula II.

Alternatively, the intermediate II (R≠H) is prepared starting from acompound of formula

R—X  (X)

wherein R is different from H and X is a chlorine, bromine or iodineatom, or a hydroxy group. When X is hydroxy, this is activated with asuitable activating agent, for example p-toluensulphonyl, according toconventional methods. This compound is reacted with a compound offormula

wherein R₁ and R₂ are as defined above, in the presence of a base suchas, for example, sodium hydride, to give a compound of formula

wherein R₁ and R₂ are as defined above and R is different from H, whichis reduced, for example with lithium aluminium hydride, to give thecompound of formula II (R≠H). Another example of synthesis relates tothe compounds of formula I wherein A is a heterocycle substituted by—Y—W on the nitrogen atom and further substituted by an oxo group. Inthis case the preparation starts from the compounds of formula

wherein R, R₁ and R₂ are as defined above and A′ is a heterocyclecontaining a nitrogen atom, optionally unsaturated and substituted by anoxo group in a suitable position. These compounds are known in theliterature or can be easily prepared by the skilled in the art. Thecompound XIII is treated with a compound of formula

W—Y—X  (XIV)

wherein W, Y and X are as defined above in the presence of sodiumhydride to give the desired compound of formula I.

The synthesis of the N-oxides of the compounds of formula I occurs bytreating the compounds of formula I with peracids such as, for example,m-chloroperbenzoic acid.

The preparation of the salts of the compounds I is effected according toconventional methods.

The compounds of formula I are selective PDE 4 inhibitors as showed bythe inhibition tests on the isolated enzyme (example 55).

It is apparent how these enzymatic selectivity and specificity featurescombined with the lack of activity on the cardiovascular system make thecompounds of formula I specifically suitable for treating pathologiesinvolving PDE 4 and TNFα even if in the present contest the interest isparticularly focused on the respiratory pathologies. In particular thecompounds of the invention are useful for treating allergic andinflammatory diseases and above all for treating emphysema, chronicobstructive pulmonary disease (COPD) and chronic bronchitisspecifically, asthma and allergic rhinithis.

The therapeutic doses shall be generally from 0.1 to 1,000 mg a day andfrom 1 to 100 mg by oral route for single administration.

A further object of the present invention are the pharmaceuticalcompositions containing a therapeutically effective amount of thecompounds of formula I or pharmaceutically acceptable salts thereof inadmixture with a suitable carrier.

The pharmaceutical compositions object of the invention can be liquid,suitable for the enteral or parenteral administration, and, preferably,solid such as tablets, capsules. granulates, suitable for the oraladministration, or in a form suitable for the transdermal and inhalatoryadministration.

The preparation of the pharmaceutical compositions object of theinvention can be effected according to common techniques.

For better illustrating the invention the following examples are nowprovided.

The ¹H-NMR spectra were run at 200 MHz on a Varian instrument: δ are inparts per million.

EXAMPLE 1 Toluen-4-sulphonic acid 5-phenyl-pentyl ester

To a solution of 5-phenyl-1-pentanol (3.28 g, 20 mmoles) andtriethylamine (6.13 ml, 44 mmoles) in CH₂Cl₂ (35 ml) under N₂,p-toluen-sulphonyl chloride (4.19 g, 22 mmoles) was added and then putunder stirring up to room temperature for 1 night. The mixture waswashed with water, NaHCO₃ and 5% HCl, anhydrified and brought to drynessto give 6.55 g of the title compound (yield: 100%).

¹H-NMR (CDCl₃): 7.79-7.10(m,9H); 4.00(t,2H,JHH=6.4 Hz); 2.58-2.51(m,2H);2.43(s,3H); 1.72-1.28(m,6H).

EXAMPLE 2 2-(3-Methoxy-phenyl)-7-phenyl-heptan-nitrile

NaH (55-65%, 880 mg, 22 mmoles) was added to a solution of3-methoxy-phenyl-acetonitrile (2.94 g, 20 mmoles) in DMF (25 ml) underN₂ and the mixture was kept under stirring for 30 minutes, thentoluen-4-sulphonic acid 5-phenyl-pentyl ester (6.37 mg, 20 mmoles),obtained as described in example 1, was added and the stirring was kepton for 1 hour. The mixture was poured into water and extracted withethyl ether. The organic phase was brought to dryness and the residuepurified by chromatography (eluent: petrolatum/ethyl ether 95:5) to give3.3 g of the title compound (yield: 56.2%).

¹H-NMR (CDCl₃): 7.31-6.81(m,9H); 3.80(s,3H); 3.75-3.67(m,1H);2.62-2.55(m,2H); 1.94-1.30(m,8H).

EXAMPLE 3 2-(3-Methoxy-phenyl)-7-phenyl-heptylamine

A solution of 2-(3-methoxy-phenyl)-7-phenyl-heptan-nitrile (3.3 g, 11.25mmoles), obtained as described in example 2, in ethyl ether (30 ml) wasadded dropwise to a suspension of LiAlH₄ (427 mg, 11.25 mmoles) inanhydrous ethyl ether (30 ml) under N₂ at room temperature. The mixturewas kept under stirring at room temperature for 1 hour. The hydride wasdecomposed with water (0.5 ml), 10% NaOH (0.75 ml) and water (1.25 ml).The mixture was filtered, washed with warm ethyl ether anhydrified andbrought to dryness to give 3.22 g of the title compound (yield: 96.2%).

¹H-NMR (CDCl₃): 7.29-6.69(m,9H); 3.79(s,3H); 2.94-2.46(m,5H);1.70-1.11(m,10H).

EXAMPLE 42-(3,5-Dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-7-phenyl-heptyl]-acetamide

A solution of (3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10mmoles) and carbonyldiimidazole (1.78 g, 11 mmoles) in THF (30 ml) waskept under stirring for 1 hour under N₂.2-(3-Methoxy-phenyl)-7-phenyl-heptylamine (2.97 g, 10 mmoles), obtainedas described in example 3, was added and the stirring was kept on for 1hour, then the mixture was brought to dryness, the residue taken up withethyl acetate and extracted with KHSO₄, NaHCO₃ and anhydrified. Afterevaporation to dryness an oil which was adsorbed on SiO₂ was obtainedand percolated with ethyl acetate/petrolatum 1:3 to give 4.57 g of thetitle compound (yield: 97.6%).

¹H-NMR (CDCl₃): 8.40(s,2H); 7.28-6.60(m,9H); 5.20(bt,1H); 3.78(s,3H);3.75(s,2H); 3.73-3.04(m,2H); 2.74-2.59(m,1H); 2.55-2.48(m,2H);1.61-1.14(m,8H).

EXAMPLE 5

1-(3,5-Dichloro-pyridin-4-ylmethyl)-6-methoxy-4-(5-phenyl-pentyl)-3,4-dihydro-isoquinolinedihydrochloride and1-(3,5-dichloro-pyridin-4-ylmethyl)-8-methoxy-4-(5-phenyl-pentyl)-3,4-dihydro-isoquinolinedihydrochloride (Compounds 1 and 2)

A solution of2-(3,5-dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-7-phenyl-heptyl]-acetamide(4.5 g, 9.27 mmoles), obtained as described in example 4, POCl₃ (3.39ml, 37.08 mmoles) in CH₃CN (45 ml) was kept under reflux for 2 hoursunder N₂, then brought to dryness and the residue taken up with water,neutralised with NaHCO₃ and extracted with CH₂Cl₂. The organic phase waswashed, anhydrified and brought to dryness to give an oil which waschromatographed to give two separated products which were salified withHCl/ethyl ether to give 2.6 g of Compound 1 (yield: 51.9%) and 0.45 g ofCompound 2 yield: 8.98%).

a) Compound 1: ¹H-NMR (DMSO): 8.71(s,2H); 8.10-7.10(m,7H);5.10-4.82(m,2H); 3.92(s,3H); 3.79-3.73(m,2H); 3.13-3.02(m,1H);2.56-2.48(m, 2H); 1.60-1.19(m,10H).

b) Compound 2: ¹H-NMR (DMSO): 8.69(s,2H); 7.81-7.04(m,8H); AB system:Va=5.00, Vb=4.75, JAB=18.8 Hz: 3.90(s,3H); 373-3.66(m,2H);3.08-2.98(m,1H); 2.53(t,2H); 1.59-1.18(m,8H).

EXAMPLE 6 Toluen-4-sulphonic acid cyclopentylmethyl ester

A solution of cyclopentan-methanol (2 g, 20 mmoles), CH₂Cl₂ (20 ml),triethylamine (5.85 ml, 42 mmoles) and p-toluen-sulphonyl chloride (4 g,21 mmoles) was kept under stirring at room temperature for 1 night, thenwashed with water, 5% HCl and NaHCO₃ and evaporated to give 5.09 g ofthe title compound (yield: 100%).

¹H-NMR (CDCl₃): 7.79-7.30(m,4H); 3.87(d, 1H,JHH=7.2 Hz); 2.43(s,3H);2.29-1.06(m,9H).

EXAMPLE 7 3-Cyclopentyl-2-(3-methoxy-phenyl)-propionitrile

By working in a way similar to that described in example 2 but usingtoluen-4-sulphonic acid cyclopentylmethyl ester (5.09 g, 20 mmoles),obtained as described in example 6, 3-methoxy-phenyl-acetonitrile (2.94g, 20 mmoles), NaH (55-65%, 880 mg, 22 mmoles) and DMF (25 ml), 2.3 g ofthe title compound were obtained (yield: 50.1%).

¹H-NMR (CDCl₃): 7.31-6.80(m,4H); 3.80(s,3H); 3.75-3.67(m,1H);2.09-1.04(m,11H).

EXAMPLE 8 3-Cyclopentyl-2-(3-methoxy-phenyl)-propylamine

A solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-propionitrile (2.3 g,10 mmoles), obtained as described in example 7, in ethyl ether (25 ml)was added to a suspension of LiAlH₄ (380 mg, 10 mmoles) in ethyl ether(30 ml), under N₂, and the mixture was kept under stirring at roomtemperature for 1 hour. The hydride was decomposed with water (0.4 ml),10% NaOH (0.5 ml) and water again (1 ml). The mixture was filtered,washed with ethyl ether and water. The organic phase was evaporated togive 2.2 g of the title compound (yield: 94.3%).

¹H-NMR (CDCl₃): 7.25-6.72(m,4H); 3.78(s,3H); 2.92-2.52(m,3H);1.76-0.95(m,11H).

EXAMPLE 9N-[3-cyclopentyl-2-(3-methoxy-phenyl]-2-(3,5-dichloro-pyridin-4-yl)-acetamide

By working in a way similar to that described in example 4 but using(3,5-dichloro-pyridin-4-yl)-acetic acid (1.94 g, 9.43 mmoles),carbonyldiimidazole (1.68 g, 10.373 mmoles), THF (30 ml) and3-cyclopentyl-2-(3-methoxy-phenyl)-propylamine (2.2 g, 9.43 mmoles),obtained as described in example 8, 3.35 g of the title compound wereobtained (yield: 98.3%), m.p.: 106-107° C.

¹H-NMR (CDCl₃): 8.41(s,2H); 7.21-6.62(m,4H); 5.15(bs,1H); 3.78(s,3H);3.75(s,2H); 3.74-3.02(m,2H); 2.79-2.65(m,1H); 2.56-2.49(m,2H);1.74-0.94(m,11H).

EXAMPLE 104-Cyclopentylmethyl-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-3,4-dihydro-isoquinolinedihydrochloride and4-cyclopentylmethyl-1-(3,5-dichloro-pyridin-4-ylmethyl)-8-methoxy-3,4-dihydro-isoquinolinedihydrochloride (Compounds 3 and 4)

By working in a way similar to that described in example 5 but usingN-[3-cyclo-pentyl-2-(3-methoxy-phenyl)-propyl]-2-(3,5-dichloro-pyridin-4-yl)-acetamide(3.2 g, 7.6 mmoles), obtained as described in example 9, POCl₃ (2.78 ml,30.4 mmoles) and CH₃CN (35 ml), 1 g of Compound 3 (yield: 27.6%) and0.37 g of Compound 4 (yield: 10.2%) were obtained.

a) Compound 3—m.p.: 162-164° C. (dec.)

¹H-NMR (DMSO): 8.71(s,2H); 8.58(bs,2H); 8.06(d,1H,JHH=8.4Hz);7.14-7.07(m,2H); AB system: VA=5.06, VB=4.88, JAB=18.3 Hz; 3.91(s,3H);3.81-3.73(m,2H); 3.14-3.03(m,1H); 1.86-1.00(m,11H).

b) Compound 4—m.p.: 189-190° C. (dec.)

¹H-NMR (DMSO): 8.71(s,2H); 7.82-7.20(m,3H); AB system: VA=5.02, VB=4.78,JAB=18.9 Hz; 3.89(s,3H); 3.76-3.69(m,2H); 3.12-3.01(m,1H);1.86-1.00(m,11H).

EXAMPLE 11 Toluen-4-sulphonic acid 6-phenyl-hexyl ester

A solution of 6-phenyl-1-hexanol (2.9 g, 16.27 mmoles), CH₂Cl₂ (30 ml),triethylamine (4.76 ml, 34.16 mmoles) and p-toluensulphonyl chloride(3.26 g, 17.08 mmoles) was kept under stirring at room temperature for 1night, washed with water, 5% HCl and NaHCO₃ and evaporated to give 5.4 gof the title compound (yield: 100%).

¹H-NMR (CDCl₃): 7.80-7.11(m,9H); 4.00(t,2H,JHH=6.4 Hz) 2.59-2.51(m,2H);2.42(s,3H); 1.68-1.21(m,8H).

EXAMPLE 12 2-(3-Methoxy-phenyl)-8-phenyl-octan-nitrile

By working in a way similar to that described in example 2 but usingtoluen-4-sulphonic acid 6-phenyl-hexyl ester (5.4 g, 16.24 mmoles),obtained as described in example 11, 3-methoxy-phenyl-acetonitrile (2.39g, 16.24 mmoles), NaH (55-65%, 715 mg, 17.86 mmoles) and DMF (25 ml),2.7 g of the title compound were obtained (yield: 54.1%).

¹H-NMR (CDCl₃): 7.32-6.82(m,9H); 3.81(s,3H); 3.76-3.68(m,1H);2.62-2.55(m,2H); 1.94-1.30(m,10H).

EXAMPLE 13 2-(3-Methoxy-phenyl)-8-phenyl-octylamine

A solution of 2-(3-methoxy-phenyl)-8-phenyl-octan-nitrile (2.7 g, 8.78mmoles), obtained as described in example 12, in ethyl ether (30 ml) wasadded to a suspension of LiAlH₄ (333 mg, 8.78 mmoles) in ethyl ether (30ml), under N₂, and the mixture was kept under stirring at roomtemperature for 1 hour. The hydride was decomposed with water (0.4 ml),10% NaOH (0.5 ml) and water again (1 ml). The mixture was filtered,washed with ethyl ether and water. The organic phase was evaporated togive 2.5 g of the title compound (yield: 91.4%).

¹H-NMR (CDCl₃): 7.29-6.70(m,9H); 3.79(s,3H); 2.93-2.45(m,5H);1.65-1.13(m,10H).

EXAMPLE 142-(3,5-Dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-8phenyl-octyl]-acetamide

By working in a way similar to that described in example 4 but using(3,5-dichloro-pyridin-4-yl)-acetic acid (1.65 g, 8.026 mmoles),carbonyldiimidazole (1.43 g, 8.829 mmoles), THF (25 ml) and2-(3-methoxy-phenyl)-8-phenyl-octylamine (2.5 g, 8.026 mmoles), obtainedas described in example 13, 3.39 g of the title compound were obtained(yield: 84.6%), m.p.: 97-98° C.

¹H-NMR (CDCl₃): 8.41(s,2H); 7.28-6.61(m,9H); 5.16(bt,1H); 3.78(s,3H);3.75(s,2H); 3.74-3.03(m,2H); 2.74-2.59(m,1H); 2.56-2.49(m,2H);1.60-1.11(m,10H).

EXAMPLE 151-(3,5-Dichloro-pyridin-4-ylmethyl)-6-methoxy-4-(6-phenyl-hexyl)-3,4-dihydro-isoquinolinedihydrochloride and1-(3,5-dichloro-pyridin-4-ylmethyl)-8-methoxy-4-(6-phenyl-hexyl)-3,4-dihydro-isoquinolinedihydrochloride (Compounds 5 and 6)

By working in a way similar to that described in example 5 but using2-(3,5-dichloropyridin-4-yl)-N-[2-(3-methoxy-phenyl)-8-phenyl-octyl]-acetamide(3.25 g, 6.51 mmoles), obtained as described in example 14, POCl₃ (2.38ml, 26.04 mmoles) and CH₃CN (35 ml), 2.32 g of Compound 5 (yield: 64.3%)and 0.3 g of Compound 6 (yield: 10.2%) were obtained.

a) Compound 5—m.p.: 135-137° C. (dec.)

¹H-NMR (DMSO): 8.72(s,2H); 8.11-7.09(m,8H); 7.77(bs, 2H); AB system:Va=5.05, Vb=4.87, JAB=18.5 Hz; 3.91(s,3H); 3.76(bs,2H); 3.12-3.03(m,1H);2.53(t,2H); 1.59-1.18(m,10H).

b) Compound 6—m.p.: 117-119° C. (dec.)

¹H-NMR (DMSO): 8.69(s,2H); 7.80-7.03(m,8H); AB system: Va=5.00, Vb=4.74,JAB=18.8 Hz); 3.89(s,3H); 3.69(broad signal,2H); 3.08-2.97(m,1H);2.54(t,2H); 1.59-1.18(m,10H).

EXAMPLE 16 2-(3-Methoxy-phenyl)-pentan-nitrile

NaH (55-65%, 1.44 g, 36 mmoles) and, after 30 minutes under stirring,1-bromo-propane (4.46 g, 36 mmoles) were added to a solution of3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles) in anhydrous DMF (30ml) under N₂ at room temperature. After 1.5 hours the mixture was pouredinto water (200 ml), extracted 3 times with ethyl ether, anhydrified andbrought to dryness to give a residue which was chromatographed (eluent:petrolatum, then petrolatum/ethyl ether 95:5) to give 4.2 g of the titlecompound (yield: 74%).

¹H-NMR (CDCl₃): 7.81-7.31(m,4H); 3.80(s,3H); 3.77-3.70(m,1H);2.00-1.38(m,2H); 0.94(t,3H,JHH=7.4 Hz).

EXAMPLE 17 2-(3-Methoxy-phenyl)-pentylamine

A solution of 2-(3-methoxyphenyl)-pentan-nitrile (4.2 g, 0.022 moles),obtained as described in example 16, in anhydrous ethyl ether (25 ml)was added dropwise to a suspension of LiAlH₄ (0.84 g, 0.022 moles) inanhydrous ethyl ether (40 ml) under N₂ at room temperature. After 2hours water (0.84 ml), 10% NaOH (1.6 ml) and water (0.84 ml) were added,it was filtered and washed with ethyl ether. The organic phase wasextracted with 10% HCl. The aqueous acid phase was basified with K₂CO₃,extracted with ethyl ether which was anhydrified and brought to drynessto give 3.9 g of the title compound (yield: 90.9%).

¹H-NMR (CDCl₃): 7.25-6.70(m,4H); 3.78(s,3H); 2.94-2.53(m,5H);2.16(bs,2H); 1.63-1.10(m,2H); 0.84(t,3H,JHH=7.4 Hz).

EXAMPLE 182-(3,5-Dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-pentyl]-acetamide

By working in a way similar to that described in example 4 but using(3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10 mmoles),carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and2-(3-methoxy-phenyl)-pentylamine (1.93 g 10 mmoles), obtained asdescribed in example 17, 3.7 g of the title compound were obtained(yield: 97%), m.p.: 97-98° C.

¹H-NMR (CDCl₃): 8.41(s,2H); 7.20-6.61(m,4H); 5.19(bt,1H); 3.78(s,3H);3.75(s,2H); 3.75-3.03(m,2H); 2.77-2.62(m,1H); 1.60-1.08 (m,4H);0.82(t,3H,JHH=7.4 Hz).

EXAMPLE 191-(3,5-Dichloro-pyridin-4-ylmethyl)-6-methoxy-4-propyl-3,4-dihydro-isoquinolinedihydrochloride and1-(3,5-dichloro-pyridin-4-ylmethyl)-8-methoxy-4-propyl-3,4-dihydro-isoquinolinedihydrochloride (Compounds 7 and 8)

By working in a way similar to that described in example 5 but using2-(3,5-dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-pentyl]-acetamide(3.4 g, 8.92 mmoles), obtained as described in example 18, POCl₃ (3.26ml, 35.66 mmoles) and CH_(3CN) (35 ml), 1.62 g of Compound 7 (yield:41.6%) and 0.44 g of Compound 8 (yield: 11.3%) were obtained.

a) Compound 7—¹H-NMR (DMSO): 8.73(s,2H); 8.12-7.10(m,3H); AB system:Va=5.06, Vb=4.88, Jab=18.5 Hz; 3.93(s,3H); 3.80-3.73(m,2H);3.19-3.04(m,1H); 1.55-1.13(m,4H); 0.87(t,3H,JHH=7.1 Hz).

b) Compound 8—¹H-NMR (DMSO): 8.70(s,2H); 7.83-7.06 (m,3H); AB system:Va=5.03, Vb=4.81, Jab=18.9 Hz; 3.87(s,3H); 3.76-3.70 (m,2H)3.15-3.04(m,1H); 1.59-1.13(m,4H); 0.91-0.83(m,3H).

EXAMPLE 20 2-(3-Methoxy-phenyl)-4-methyl-pentan-nitrile

By working in a way similar to that described in example 16 but using3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (30 ml),NaH (55-65%, 1.44 g, 36 mmoles) and isobutylbromide (4.97 g, 36 mmoles),3.8 g of the title compound were obtained (yield: 62.3%).

EXAMPLE 21 2-(3-Methoxy-phenyl)-4-methyl-pentylamine

By working in a way similar to that described in example 17 but usingLiAlH₄ (0.7 g, 0.018 moles) in anhydrous ethyl ether (35 ml) and2-(3-methoxy-phenyl)-4-methyl-pentan-nitrile (3.8 g, 0.018 moles),obtained as described in example 20, in anhydrous ethyl ether (35 ml),3.5 g of the title compound were obtained (yield: 90.4%).

¹H-NMR (CDCl₃): 7.25-6.71(m,4H); 3.78(s,3H); 2.89-2.57(m,3H);1.61-1.33(m,5H); 0.82(m,6H).

EXAMPLE 222-(3,5-Dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-4-methyl-pentyl]-acetamide

By working in a way similar to that described in example 4 but using(3,5-dichloropyridin-4-yl)-acetic acid (2.06 g, 10 mmoles),carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and2-(3-methoxy-phenyl)-4-methyl-pentylamine (2.07 g, 10 mmoles), obtainedas described in example 21, 3.85 g of the title compound were obtained(yield: 97.6%), m.p.: 98-99° C.

¹H-NMR (CDCl₃): 8.41(s,2H); 7.21-6.62(m,4H); 5.20(bt,1H); 3.78(s,3H);3.75(s,2H); 43.7-3.00(m,2H); 2.85-2.71(m,1H); 1.59-1.30(m,3H);0.83-0.79(m,6H).

EXAMPLE 231-(3,5-Dichloro-pyridin-4-ylmethyl)-4-isobutyl-6-methoxy-3,4-dihydro-isoquinolinedihydrochloride and1-(3,5-dichioro-pyridin-4-ylmethyl)-4-isobutyl-8-methoxy-3,4-dihydro-isoquinolinedihydrochloride (Compounds 9 and 10)

By working in a way similar to that described in example 5 but using2-(3,5-dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-4-methyl-pentyl]-acetamide(3.4 g, 8.6 mmoles), obtained as described in example 22, POCl₃ (3.15ml, 34.4 mmoles) and CH₃CN (35 ml), 1.37 g of Compound 9 (yield: 35.4%)and 0.4 g of Compound 10 (yield: 10.3%).

a) Compound 9—¹H-NMR (DMSO): 12.45(bs,1H); 8.75(s,2H); 8.15-7.07(m,3H);AB system: Va=5.05, Vb=4.89, Jab=18.5 Hz; 3.93(s,3H); 3.84-3.67(m,2H);3.22-3.09(m,1H); 1.62-1.28(m,3H); 0.94-0.86(m,6H).

b) Compound 10—¹H-NMR (DMSO): 8.72(s,2H); 7.82-7.05 (m,3H); AB system:Va=5.03, Vb=4.78, Jab=18.9 Hz: 3.91(s,3H); 3.74-3.68 (m,2H);3.20-3.07(m,1H); 1.60-1.43(m,1H); 1.39-1.30(m,2H) 0.94-0.85(m,6H).

EXAMPLE 24 2-(3-Methoxy-phenyl)-butyronitrile

By working in a way similar to that described in example 16 but using3-methoxy-phenyl-acetonitrile (8.8 g, 60 mmoles), DMF (60 ml), NaH (60%,2.88 g, 72 mmoles) and ethylbromide (7.85 g, 72 mmoles), andchromatographing with petrolatum/ethyl ether 97:3 as eluent, 6.1 g ofthe title compound were obtained (yield: 58%).

¹H-NMR (CDCl₃): 7.31-6.81(m,4H); 3.80(s,3H); 3.60(t,1H,JHH=7.2 Hz);2.00-1.85(m,2H); 1.06(t,3H,JHH=7.4 Hz).

EXAMPLE 25 2-(3-Methoxy-phenyl)-butylamine

A solution of 2-(3-methoxy-phenyl)-butyronitrile (6.1 g, 35 mmoles),obtained as described in example 24, in ethyl ether (20 ml) was addeddropwise to a suspension of LiAlH₄ (1.32 g, 35 mmoles) in ethyl ether(40 ml) under N₂ at room temperature. After 1 hour the hydride wasdecomposed with water (1.3 ml), 10% NaOH (2.6 ml) and water (1.3 ml).The mixture was filtered, washed with ethyl ether, dried and evaporatedto give the title compound. The mother liquors were concentrated, addedwith triethanolamine (3 ml), kept under stirring for some hours,extracted more times with ethyl ether and the organic phase wasevaporated. The residue was joined to the previous compound and thewhole was chromatographed to give 4.8 g of the title compound (yield:77%).

¹H-NMR (CDCl₃): 7.24-6.69(m,4H); 3.78(s,3H);, 2.94-2.73 (m,2H);2.51-2.37(m,1H); 1.76-1.40(m,2H); 1.22(s,2H); 0.79(t,3H,JHH=7.4 Hz).

EXAMPLE 262-(3,5-Dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-butyl]-acetamide

By working in a way similar to that described in example 4 but using(3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10 mmoles),carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and2-(3-methoxy-phenyl)-butylamine (1.79 g, 10 mmoles), obtained asdescribed in example 25, 3.55 g of the title compound were obtained(yield: 96.7%). m.p.: 104-105° C.

¹H-NMR (CDCl₃): 8.41(s,2H); 7.21-6.60(m,4H); 5.21(bs,1H); 3.78(s,3H);3.75(s,2H);3.76-3.06(m,2H); 2.67-2.52(m,1H); 1.72-1.44(m,2H);0.74(t,3H,JHH=7.4 Hz).

EXAMPLE 271-(3,5-Dichloro-pyridin-4-ylmethyl)-4-ethyl-6-methoxy-3,4-dihydro-isoquinolinedihydro-chloride and1-(3,5-dichloro-pyridin-4-ylmethyl)-4-ethyl-8-methoxy-3,4-dihydro-iso-quinolinedihydrochloride (Compounds 11 and 12)

By working in a way similar to that described in example 5 but using2-(3,5-dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-butyl]-acetamide(3.35 g, 9.12 mmoles), obtained as described in example 26, POCl₃ (3.34ml, 36.5 mmoles) and CH₃CN (35 ml), 2.65 g of Compound 11 (yield: 68.8%)and 0.5 g of Compound 12 (yield: 14.5%) were obtained.

a) Compound 11—¹H-NMR (DMSO): 12.6(bs,2H); 8.73 (s,2H); 8.12-7.1(m,3H);AB system: Va=5.05, Vb=4.88, Jab=18.4 Hz; 3.93(s,3H); 3.88-3.68(m,2H);3.08-2.96(m,1H); 1.63-1.48(m,2H); 0.89(t,3H,JHH=7.4 Hz).

b) Compound 12—¹H-NMR (DMSO): 12.8(bs,1H); 8.70(s,2H); 7.81-7.08(m,3H);AB system: Va=5.01, Vb=4.77, Jab=18.8 Hz; 3.89(s,3H); 3.80-3.63(m,2H);3.04-2.92(m,H); 1.67-1.43(m,2H); 0.89(t,3H,JHH=7.3 Hz)

EXAMPLE 28 2-(3-Methoxy-phenyl)-4phenyl-butyronitrile

By working in a way similar to that described in example 16 but using3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (30 ml),NaH (55-65%, 1.44 g, 36 mmoles) and 2-bromoethylbenzene (6.7 g, 36.3mmoles), 4.8 g of the title compound were obtained (yield: 64%).

¹H-NMR (DMSO): 7.37-6.82(m,9H); 3.80(s,3H); 3.73-3.65(m,1H);2.91-2.69(m,2H); 2.35-2.05(m,2H).

EXAMPLE 29 2-(3-Methoxy-phenyl)-4-phenyl-butylamine

A solution of 2-(3-methoxy-phenyl)-4-phenyl-butyronitrile (4.7 g, 18.7mmoles), obtained as described in example 28, in anhydrous ethyl ether(50 ml) was dropwise added to a suspension of LiAlH₄ (0.71 g, 0.0187moles) in anhydrous ethyl ether (20 ml) under N₂ in a water/ice bath tokeep at room temperature. The mixture was kept under N₂ for 1 hour atroom temperature, then water (0.7 ml), 20% NaOH (0.7 ml) and water again(2.1 ml) were added, the whole was filtered and washed more times withwarm ethyl ether. The filtrate was extracted with 10% HCl, the aqueousphase basified with K₂CO₃, extracted with ethyl ether, anhydnfied andbrought to dryness to give 4.4 g of the title compound (yield: 92.1%).

¹H-NMR (CDCl₃): 7.29-6.73(m,9H); 3.80(s,3H); 3.00-2.76(m,2H);2.63-1.76(m,5H); 1.08(bs).

EXAMPLE 302-(3,5-Dichloro-pyridin-4-yl)-N-[1-(3-methoxy-phenyl)-3-phenyl-propyl]-acetamide

A solution of (3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10mmoles) and carbonyldiimidazole (1.78 g, 11 mmoles) in THF (30 ml) waskept under stirring for 1 hour under N₂.2-(3-Methoxy-phenyl)-4-phenyl-butylamine (2.55 g, 10 mmoles), obtainedas described in example 29, was added and the stirring went on for 1hour. The mixture was brought to dryness, the residue partitionedbetween ethyl acetate and aqueous KHSO₄. The organic phase was washedwith NaHCO³⁻ and dried. After evaporation to residue, it was obtained anoil which, adsorbed on SiO₂ and percolated with ethyl acetate/petrolatum1:3, gave 4.1 g of the title compound (yield: 92.5%).

¹H-NMR (CDCl₃): 8.42(s,2H); 7.27-6.64(m,9H) 5.17(bt,1H); 3.80(s,3H);3.76(s,2H); 3.75-3.12(m,2H); 2.80-2.65(m,1H); 2.51-2.43 (m,2H);2.01-1.79(m,2H).

EXAMPLE 313-(3,5-Dichloro-pyridin4-ylmethyl)-7-methoxy-1-phenylethyl-1,4-dihydro-isoluinolinedihydrochloride and3-(3,5-dichloro-pyridin-4-ylmethyl)-5-methoxy-1-phenylethyl-1,4-dihydro-isoquinolinedihydrochloride (Compounds 13 and 14)

By working in a way similar to that described in example 5 but using2-(3,5-dichloropyridin-4-yl)-N-[1-(3-methoxy-phenyl)-3-phenyl-propyl]-acetamide(4 g, 9.02 mmoles), obtained as described in example 30, POCl₃ (3.3 ml,36.08 mmoles) and CH₃CN (40 ml), 1.84 g of Compound 13 (yield: 40.9%)and 0.59 g of Compound 14 (yield: 14.2%) were obtained.

a) Compound 13—¹H-NMR (DMSO): 12.74(bs); 8.73(s,2H); 8.12-7.11(m,8H);5.12-4.85(m,2H); 3.93(s,3H); 3.88-3.82(m,2H); 3.22-3.10(m,1H);2.79-2.53(m,2H); 1.90-1.78(m,2H).

b) Compound 14—¹H-NMR (DMSO): 18.71(s,2H); 7.82-7.08(m,8H);5.07-4.73(m,2H); 3.90(s,3H); 3.82-3.74(m,2H); 3.17-3.05(m,1H); 2.82-2.51(m,2H); 1.87-1.74(m,2H).

EXAMPLE 32 Cyclopentyl-(3-methoxy-phenyl)-acetonitrile

By working in a way similar to that described in example 16 but using3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (30 ml),NaH (55-65%, 1.44 g, 36.3 mmoles) and bromocyclopentane (5.4 g, 36.3mmoles), 5.8 g of the title compound were obtained (yield: 90%).

¹H-NMR (CDCl₃): 7.29-6.80(m,4H); 3.77(s,3H); 3.79(s,3H)3.66(s,1H,JHH=7.8Hz); 2.38-2.18(m,1H); 1.92-1.18(m,8H).

EXAMPLE 33 2-Cyclopentyl-2-(3-methoxy-phenyl)-ethylamine

By working in a way similar to that described in example 29 but usingLiAlH₄ (1.01 g, 26.57 mmoles) in anhydrous ethyl ether (20 ml) andcyclopentyl-(3-methoxy-phenyl)-acetonitrile (5.72 g, 26.57 mmoles),obtained as described in example 32, 5 g of the title compound wereobtained (yield: 85.8%).

¹H-NMR (CDCl₃): 7.23-6.71(m,4H); 3.78(s,3H); 3.06-2.76(m,2H);2.36-2.24(m,1H); 2.06-0.88(m,13H).

EXAMPLE 34N-[cyclopentyl-(3-methoxy-phenyl)-methyl]-2-(3,5-dichloro-pyridin-4-yl)-acetamide

By working in a way similar to that described in example 30 but using(3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10 mmoles),carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and2-cyclopentyl-2-(3-methoxy-phenyl)-ethylamine (2.19 g, 10 mmoles),obtained as described in example 33, 3.8 g of the title compound wereobtained (yield: 98.2%), m.p.: 105-106° C.

¹H-NMR (CDCl₃): 8.39(s,2H); 7.19-6.59(m,4H); 5.08(bs,1H);3.95-3.02(m,2H); 3.78(s,3H); 3.72(s,2H); 2.49-2.37(m,1H);2.04-0.87(m,9H).

EXAMPLE 351-Cyclopentyl-3-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,4-dihydro-isoquinolinedihydrochloride and1-cyclopentyl-3-(3,5-dichloro-pyridin-4-ylmethyl)-5-methoxy-1,4-dihydro-isoquinolinedihydrochloride (Compounds 15 and 16)

A solution ofN-[cyclopentyl-(3-methoxy-phenyl)-methyl]-2-(3,5-dichloro-pyridin-4-yl)-acetamide(3.6 g, 8.84 mmoles), obtained as described in example 34, and POCl₃(3.24 ml, 35.35 mmoles) in CH₃CN (40 ml) was kept under reflux for 2hours under N₂, brought to dryness and the residue was taken up withwater, neutralised with NaHCO₃ and extracted with CH₂Cl₂. The organicphase was washed brought to dryness and the residue chromatographed(eluent: petrolatum/ethyl acetate 9:1 then 7:3) to give 2 compoundswhich were salified with HCl/ethyl ether to give 0.46 g of Compound 16(yield: 12.2%) and a portion of the second compound which was digestedwith CH₃CN (15 ml), dissolved in water, basified and extracted withethyl ether. The organic phase was anhydrified and brought to drynessand the residue, dissolved in ethyl ether and salified with HCl/ethylether, gave 2.2 g of Compound 15 (yield: 53.8%).

a) Compound 15: ¹H-NMR (DMSO): 12.6(bs,2H); 8.74(s,2H); 8.17-7.11(m,3H);AB system: Va=5.09, Vb=4.85, Jab=18.4 Hz; 3.93(s,3H); 3.89-3.71(m,2H);2.92-2.83(m,1H); 1.95-1.15(m,9H).

b) Compound 16: ¹H-NMR (DMSO): 12.42(bs), 8.73(s,2H); 7.79-7.06(m,3H);5.10-4.67(m,2H); 3.92(s,3H); 3.84-3.65(m,2H); 2.85-2.74(m, 1H);1.92-1.14(m,9H).

EXAMPLE 36 2-(3-Methoxy-phenyl)-3-methyl-butyronitrile

By working in a way similar to that described in example 16 but using3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (40 ml),NaH (55-65%, 1.44 g, 36.3 mmoles) and 2-bromo-propane (4.46 g, 36.3mmoles), 4.53 g of the title compound were obtained (yield: 79.9%).

EXAMPLE 37 2-(3-Methoxy-phenyl)-3-methyl-butylamine

A solution of 2-(3-methoxy-phenyl)-3-methyl-butyronitrile (4.53 g, 23.93mmoles), obtained as described in example 36, in ethyl ether (40 ml) wasadded dropwise to a suspension of LiAlH₄ (1 g, 23.93 mmoles) in ethylether (20 ml) under N₂ at room temperature. After 1 hour under stirringthe whole was cooled in a water/ice bath and the hydride was decomposedwith water (1 ml), 20% NaOH (1 ml) and water (3 ml). The mixture waskept under stirring for 1 hour, filtered, the filtrate washed with waterand ether. The organic phase was evaporated to give 4.53 g of the titlecompound (yield: 47%).

¹H-NMR (CDCl₃): 7.20-6.67(m,4H); 3.77(s,3H); 3.08-2.79(m,2H);2.31-2.19(m,1H); 1.89-1.71(m,1H); 0.95 and 0.70(2s,6H,JHH=6.4 Hz).

EXAMPLE 382-(3,5-Dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-3-methyl-butyl]-acetamide

By working in a way similar to that described in example 30 but using(3,5-dichloro-pyridin-4-yl)-acetic acid (4.62 g, 22.4 mmoles),carbonyldiimidazole (4 g, 24.64 mmoles), THF (60 ml) and2-(3-methoxy-phenyl)-3-methyl-butylamine (4.33 g, 22.4 mmoles), obtainedas described in example 37, 8.36 g of the title compound were obtained(yield: 97.9%), m.p.: 94-95° C.

¹H-NMR (CDCl₃): 8.36(s,2H); 7.19-6.54(m,4H); 5.05(bs,1H);4.00-3.04(m,2H); 3.77(s,3H); 3.70(s,2H); 2.46-2.30(m,1H);1.90-1.66(m,1H); 0.98 and 0.68(2d,6H,JHH=6.8 Hz).

EXAMPLE 391-(3,5-Dichloro-pyridin-4-ylmethyl)-4-isopropyl-6-methoxy-3,4-dihydro-isoquinolineand1-(3,5-dichloro-pyridin-4-ylmethyl)-4-isopropyl-8-methoxy-3,4-dihydro-isoquinoline(Compounds 17 and 18)

By working in a way similar to that described in example 5 but using2-(3,5-dichloropyridin-4-yl)-N-[2-(3-methoxy-phenyl)-3-methyl-butyl]-acetamide(8.1 g, 21.24 mmoles), obtained as described in example 38, POCl₃ (2.54ml, 27.72 mmoles) and CH₃CN (80 ml), 5.9 g of Compound 17 (yield: 76.5%)and 1.1 g of Compound 18 (yield: 11.4%) were obtained.

a) Compound 17—¹H-NMR (CDCl₃): 8.45(s,2H); 7.56-6.70(m,3H);4.50-4.10(m,2H); 4.03-3.28(m,2H); 3.85(s,3H); 2.31-2.22(m,1H);1.90-1.72(m, 1H); 0.89 and 0.82(2d,6H,JHH=6.6 Hz).

b) Compound 18—¹H-NMR (DMSO): 8.72(s,2H); 7.83-7.06(m,3H);5.13-4.72(m,2H); 3.91(s,3H); 3.85-3.64(m,2H); 2.79-2.71(m,1H);1.89-1.71(m,1H); 0.92 and 0.84(2d,6H,JHH=6.6 Hz).

EXAMPLE 40 1-Methoxy-3-(2-nitro-vinyl)-benzene

Methylamine (8.03M in ethanol, 2.5 ml) and nitromethane (11.8 ml, 0.22moles) were added to a solution of 3-methoxy-benzaldheyde (27.2 g, 0.2moles) in methanol (83 ml) and the mixture was kept standing at dark for72 hours. The resultant precipitate was filtered, washed with methanoland dried to give 15.5 g of the title compound (yield: 43.29%).

¹H-NMR (CDCl₃): 7.96(d,1H,JHH=13.8 Hz); 7.55(d,1H); 7.39-7.00(m,4H)3.83(s,3H).

EXAMPLE 41 1-Methoxy-3-(1-phenyl-2-nitro-propyl)-benzene

A solution of 1-methoxy-3-(2-nitro-vinyl)-benzene (9.3 g, 5.9 mmoles),obtained as described in example 40, in THF (90 ml) was added dropwiseto a solution of phenyl-magnesium chloride (2N in THF, 38.9 ml, 77.85mmoles) under N₂ at −28° C. and the mixture was kept under stirring for10 minutes, then 5% HCl (100 ml) was added and the stirring went on for30 minutes. The phases were separated and the acid one was extractedwith ethyl ether and brought to dryness to give a residue which waschromatographed (eluent: petrolatum, then petrolatum/ethyl ether 9:1) togive 6 g of the title compound (yield: 44.9%).

¹H-NMR (CDCl₃): 7.36-6.75(m,9H); 4.98-4.8 1(m,3H); 3.75(s,3H).

EXAMPLE 42 2-(3-Methoxy-phenyl)-2-phenyl-ethylamine

A mixture of 1-methoxy-3-(1-phenyl-2-nitro-propyl)-benzene (7.8 g, 30.33mmoles), obtained as described in example 41, ammonium formate (9.56 g,151.6 mmoles), methanol (80 ml), 10% Pd/C (1.8 g) and 3A molecularsieves (15 g) was kept under reflux for 2 hours, then filtered overcelite by washing with methanol and brought to dryness. The residue wastaken up with ethyl ether and extracted with 10% HCl. The aqueous phasewas basified with K₂CO₃ and re-extracted with ethyl ether. The organicphase was anhydrified and brought to dryness to give 5.4 g of the titlecompound (yield: 78.4%).

¹H-NMR (CDCl₃): 7.33-6.71(m,9H); 3.94(t,1H,JHH=7.4 Hz); 3.76(s,3H);3.30(d,2H).

EXAMPLE 432-(3,5-Dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-2-phenyl-ethyl]-acetamide

By working in a way similar to that described in example 4 but using(3.5-dichloro-pyridin-4-yl)-acetic acid (5.15 g, 25 mmoles),carbonyldiimidazole (4.24 g, 26.14 mmoles), THF (75 ml) and2-(3-methoxy-phenyl)-2-phenyl-ethylamine (5.4 g, 23.76 mmoles), obtainedas described in example 42, 8.9 g of the title compound were obtained(yield: 85.7%), m.p.: 142-143° C.

¹H-NMR (CDCl₃): 8.40(s,2H) 7.31-6.70(m,9H); 5.39(bt,1H);4.16-3.81(m,3H); 3.77(s,2H); 3.74(s,3H).

EXAMPLE 441-(3,5-Dichloro-pyridin-4-ylmethyl)-6-methoxy-4-phenyl-3,4-dihydro-isoquinolinedihydro-chloride (Compound 19)

A solution of2-(3,5-dichloro-pyridin-4-yl)-N-[2-(3-methoxy-phenyl)-2-phenyl-ethyl]-acetamide(8.8 g, 0.0212 moles), obtained as described in example 43, and POCl₃(7.76 mg, 0.0848 moles) in CH₃CN (100 ml) was kept under reflux under N₂for 3 hours, then brought to dryness and the residue was partitionedbetween NaHCO₃ and ethyl acetate. The organic phase was washed,anhydrified and brought to dryness to give a residue which was taken upwith CH₃CN and acidified vwith HCl/ethyl ether, then brought to residue.This was crystallised from CH₃CN (60 ml) and, after 2 hours inwater/ice, was recrystallised from CH₃CN (190 ml), then dissolved inwater, basified with K₂CO₃ and extracted with ethyl ether. The solutionwas brought to dryness and the residue triturated in petrolatum andbrought to dryness to give a portion of the compound. The mother liquorswere recrystallised and chromatographed to give a furter portion ofcompound which, joined to the previous one, summed up to 6.12 g of thetitle compound (yield: 73.8%), m.p.: 136-137° C.

¹H-NMR (CDCl₃): 8.40(s,2H); 7.31-6.70(m,9H); 5.39(bt,1H);4.16-3.81(m,3H); 3.77(s,2H); 3.74(s,3H).

EXAMPLE 45 Trifluoromethanesulphonic acid 2-formyl-6-methoxy-phenylester

Triflic anhydride (6.64 ml, 0.0395 moles) was added to a solution of2-hydroxy-3-methoxy-benzaldheyde (5 g, 0.0329 moles) in CH₂Cl₂ (50 ml)and pyridine (13.25 ml, 0.164 moles) under N₂ at −5-0° C. After 30minutes the mixture was diluted with CH₂Cl₂, washed up to acidity with5% citric acid, water, anhydrified and brought to dryness. The residuewas taken up with petrolatum (50 ml) and solidified by cooling with ice,then was filtered by washing with iced petrolatum and dried under vacuumon P₂O₅ to give 7.52 g of the title compound (yield: 80%).

EXAMPLE 46 2-Cyclopent-1-enylmethyl-3-methoxy-benzaldheyde

A solution of trifluoromethanesulphonic acid 2-formyl-6-methoxy-phenylester (6.84 g, 24.06 mmoles), obtained as described in example 45,methylencyclopentane (3.8 ml, 36.08 mmoles),bis(triphenylphosphine)PdCl₂ (844.5 mg, 1.203 mmoles), triethylamine(13.39 ml, 96.24 mmoles) in anhydrous DMF (50 ml) was heated at 90° C.under N₂ and stirring for 4 days, then poured into water and extractedwith ethyl acetate. The organic phase was washed with water, anhydrifiedand brought to dryness. The residue was flash chromatographed (eluent:petrolaturn/ethyl acetate 98:2) to give 810 mg of the title compound(yield 15%).

¹H-NMR (CDCl₃): 10.31 and 10.23 (2s,1H); 7.50-7.05(m,3H); 3.85 and3.84(2s,3H).

EXAMPLE 47 2-Cylopent-1-enylmethyl-1-methoxy-3-(2-nitro-vinyl)-benzene

Acetic acid (39.66 μl, 0.694 mmoles), methylamine (8.03M in ethanol,86.42 μl, 0.694 mmoles) and nitromethane (205.2 μl, 3.82 mmoles) wereadded, under stirring, to a solution of2-cyclopent-1-enylmethyl-3-methoxy-benzaldheyde (750 mg, 3.47 mmoles),obtained as described in example 46, in methanol (10 ml) and thestirring went on for 28 hours at 40° C. The mixture was brought todryness and the residue flash chromatographed (eluent: petrolatum/ethylacetate 7:3) to give 600 mg of the title compound (yield: 67%).

EXAMPLE 48 2-(2-Cyclopent-1-enylmethyl-3-methoxy-phenyl)-ethylaminehydrochloride

A solution of2-cyclopent-1-enylmethyl-1-metboxy-3-(2-nitro-vinyl)-benzene (0.6 g,2.31 mmoles), obtained as described in example 47, in anhydrous THF (6ml) was added dropwise under stirring to a suspension of LiAlH₄ (263 mg,6.93 mmoles) in anhydrous THF (10 ml) under N₂. The mixture was keptboiling for 1 hour, then cooled in ice and decomposed with water (0.263ml), 15% NaOH (0.263 ml) and water (0.789 ml). The mixture was stirredfor 1 hour, filtered and evaporated. The residue was dissolved in ethylacetate, washed with water, dried and acidified with HCl/ethyl acetate,then evaporated. taken up with ether and crystallised, filtered anddried under vacuum at 40° C. to give 390 mg of the title compound(yield: 63%).

EXAMPLE 49 2-(2-Cyclopentylmethyl-3-methoxy-phenyl)-ethylamine

A solution of 2-(2-cyclopent-1-enylmethyl-3-methoxy-phenyl)-vinylamine(90 mg, 1.46 mmoles), obtained as described in example 48, in methanol(20 ml) was hydrogenated in Parr in the presence of 10% Pd/C (40 mg) for2 hours. The mixture was filtered and brought to dryness to give 390 mgof the title compound (quantitative yield).

¹H-NMR (CDCl₃): 8.45(s,1H); 7.13-6.71(m,3H); 3.75(s,3H); 3.15(s,4H);2.67(d,2H,JHH=7.4 Hz); 2.08-1.16(m,9H).

EXAMPLE 50N-[2-(2-cyclopentylmethyl-3-methoxy-phenyl)ethyl]-2-(3,5-dichloropyridin-4-yl)-acetamide

By working in a way similar to that described in example 4 but using(3,5-dichloro-pyridin-4-yl)-acetic acid (356 mg, 1.73 mmoles),carbonyldiimidazole (308 mg, 1.9 mmoles), THF (15 ml),2-(2-cyclopentylmethyl-3-methoxy-phenyl)-ethylamine (390 mg, 1.44mmoles), obtained as described in example 49, and triethylamine (0.24ml, 1.73 mmoles), 520 mg of the title compound were obtained (yield:86%).

¹H-NMR (CDCl₃): 8.46(s,2H); 7.09-6.65(m,3H); 5.38(bs,1H); 3.83(s,2H);3.78(s,3H); 3.52-3.42(m,2H); 2.86(t,2H,JHH=6.8 Hz); 2.60(d,2H,JHH=7.4Hz); 2.05-1.12(m,9H).

EXAMPLE 515-Cyclopentylmethyl-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-3,4-dihydro-isoquinoline(Compound 20)

A solution ofN-[2-(2-cyclopentylmethyl-3-methoxy-phenyl)-ethyl]-2-(3,5-dichloro-pyridin-4-yl)-acetamide(520 mg, 1.23 mmoles), obtained as described in example 50, and POCl₃(0.236 ml, 2.68 mmoles) in CH₃CN (20 ml) under N₂ was kept under refluxand stirring for 3 hours, then brought to dryness and the residuedissolved in CH₂Cl₂, washed with 0.5 N NaOH then with water, anhydrifiedand brought to dryness. The residue was flash chromatographed (eluent:CH₂Cl₂/CH₃OH 98:2). The fractions containing the compound were broughtto dryness and taken up with petrolatum, then evaporated to give a solidwhich was taken up with petrolatum, filtered and dried under vacuum at40° C. to give 360 mg of the title compound (yield: 73%).

¹H-NMR (CDCl₃): 8.45(s,2H); 7.46(d,1H,JHH=8.5 Hz); 6.79(d,1H);4.3(m,2H); 3.85(s,3H); 3.55-3.45(m,2H); 2.72-2.58(m,4H);2.08-1.89(m,1H); 1.74-1.11 (m,8H).

EXAMPLE 525-Cyclopentylmethyl-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-3,4-dihydro-isoquinoline-2-oxide(Compound 21)

To a solution of5-cyclopentylmethyl-1-(3,5-dichloro-pyridin-4-ylmethNl)-6-methoxy-3,4-dihydro-isoquinoline(310 mg, 0.77 mmoles), obtained as described in example 51, in CH₂Cl₂(10 ml), 55% m-chloro-perbenzoic acid (266 mg, 0.85 mmoles) was added.The mixture was kept under stirring for 1 night, then added with further55% m-chloro-perbenzoic acid (53 mg, 0.3 mmoles). The mixture wasdiluted with CH₂Cl₂, washed with a NaHCO₃ solution, then with water,anhydrified and brought to dryness. The residue was flashchromatographed (eluent: CH₂Cl₂ with 3% CH₃OH). The eluate was taken upwith petrolatum, filtered and dried at 40° C. under vacuum to give 110mg of the title compound (yield: 34%). m.p.: 176-178° C.

¹H-NMR (CDCl₃): 12.6(bs,2H); 8.74(s,2H); 8.17-7.11(m,3H); AB system:Va=5.09, Vb=4.85, Jab=18.4 Hz; 3.93(s,3H); 3.89-3.71(m,2H);2.92-2.83(m,1H); 1.95-1.15(m,9H).

EXAMPLE 53 6-Methoxy-4-phenyl-1-pyridyl-4-ylmethyl-1H-quinolin-2-one(Compound 22)

NaH (605.96 mg, 2.4 mmoles) was added at 55° C. to a suspension of6-methoxy-4-phenyl-1H-quinolin-2-one (502 mg, 2 mmoles), obtained asdescribed in Chem. Pharm. Bull., 37, 190, (1989), in DMF (9 ml) and thewhole was kept under stirring for 45 minutes. Meanwhile,4-chloro-methyl-pyridine hydrochloride (517 mg, 3.15 mmoles) waspartitioned between 10% NaOH and CH₂Cl₂, the organic phase was washed,anhydrified and brought to dryness at room temperature under vacuum. Theresultant oil was taken up with DMF (2 ml) and added to the quinolinonesolution. The mixture was kept under stirring at room temperature for 2hours, then poured into water (50 ml); extracted with ethyl acetate, theorganic phase was washed with water, anhydrified and brought to dryness.The residue was chromatographed (eluent: petrolatum/ethyl acetate 1:1)to give 0.19 g of the title compound (yield: 55.5%).

¹H-NMR (CDCl₃): 8.55-8.52(m,2H); 7.52-7.43(m,5H); 7.16-7.12(m,2H);7.07-7.01(m,3H); 6.75(s,1H); 5.58(broad-s,2H); 3.67(s,3H).

EXAMPLE 541-(3,5-Dichloropyridin-4-ylmethyl)-6-methoxy-4-phenyl-1H-quinolin-2-one(Compound 23)

6-Methoxy-4-phenyl-1H-quinolin-2-one (1.09 g, 4.35 mmoles), obtained asdescribed in Chem. Pharm. Bull., 37, 190 (1989), was added to asuspension of potassium t-butoxide (0.154 g, 4.58 mmoles) in t-butanol(15 ml) and the mixture was heated at 60° C. for 1 hour, then brought toroom temperature and added with 3,5-dichloro-4-chloromethyl-pyridine(0.9 g, 4.58 mmoles). The mixture wvas heated at 60° C. for a night,then poured into water and extracted with ethyl acetate. The organicphase was brought to residue and the solid was chromatographed (eluent:gradient from petrolatum to petrolatum/ethyl acetate 6:4) to give 0.78 gof Compound 23 (yield: 43.6%). m.p.: 191-192° C.

¹H-NMR (CDCl₃): 8.43(s,2H); 7.52-7.40(m,5H); 7.05-6.93(m,3H);6.68(s,1H); 5.87(s,2H); 3.67(s,3H).

EXAMPLE 55

Evaluation of the PDE 4 Enzyme Inhibition

a) Purification of Human Polymorphonucleate Leukocytes

The polymorphonucleate leukocytes (PMNs) were isolated from peripheralblood of healthy volunteers according to what described by Boyum A.,Scand. J. Immunol., 1976, 5th suppl., 9). Shortly, the isolation of thePMNs was effected by Ficoll-Paque gradient centrifugation followed bysedimentation on dextrane and the erythrocyte contamination waseliminated by hypotonic lysis.

b) PDE 4 Enzyme Purification

The human PMNs were re-suspended in TRIS/HCl buffer (10 mM pH 7.8)containing MgCl₂ (5 mM), EGTA (4 mM), mercaptoethanol (5 mM),TRITON-X100 (1%), pepstatin A (1 μM), PMSF (100 μM) and leupeptin (1μM), and homogenised by Polytron. The homogenate was centrifuged at25,000×g for 30 minutes at 4° C. and the supernatant was used for thePDE 4 enzyme purification by ion exchange chromatography using the FPLCtechnique according to what described by Schudt C. et al.,Naunyn-Schmidberg's Arch. Pharmacol., 1991, 334, 682. The supernatantwas seeded on an UNO Q12 column (Bio-Rad) and the enzyme was eluted bysodium acetate gradient from 50 mM to 1M. The fractions containingenzymatic activity were collected, dialysed against water andconcentrated. The resulting PDE 4 enzyme was stored at −20° C. in thepresence of ethylenglycole (30% v/v) until the use.

c) PDE 4 Enzyme Inhibition

The enzyme activity was evaluated with an Amersham kit based on the SPA(Scintillation Proximity Assay) technique. The enzymatic reaction waseffected in a total volume of 100 μl of TRIS/HCl buffer (50 mM, pH7.5),MgCl₂ (8.3 mM), EGTA (1.7 mM), cAMP (1 μM) and [³H]cAMP (˜100.000 dpm)as tracer. The compounds of the invention were added at the selectedconcentrations. The reaction was started by adding the enzyme (15 μgprotein/ml), went on for 40 minutes at 30° C. and stopped by adding 50μl of suspension of SPA particles. The radioactivity due to theparticles was measured in a β-emitting counter. The results areexpressed as percent activity versus the control present in eachexperiment. The IC₅₀ values were calculated over 9 concentrationsequidistant in logarithmic scale using a 4-parameters logistic functionby software. The compounds of the present invention showedpharmacologically significant IC₅₀ values: for example, Compound 20 gavea value of IC₅₀=35.9±4.7 nM.

What is claimed is:
 1. A compound of formula I:

wherein A is a 6-membered unsaturated or saturated heterocyclecontaining a nitrogen atom that may be optionally substituted by an oxogroup (═O); R is: hydrogen, (C₄₋₇)cycloalkyl, aryl selected from phenyl,napthyl or indanyl; (C₁₋₈)alkyl optionally branched and/or substitutedby (C₄₋₇) cycloalkyl or aryl selected from phenyl, naphthyl or indanyl;Y is methylene or ethylene; W is a heterocycle optionally substituted bya halogen, (C₁₋₄)alkyl, hydroxy, nitro or carboxy; R₁ is: hydrogen,(C₄₋₇)cycloalkyl or a (C₂₋₈)alkyl optionally substituted by(C₄₋₇)cycloalkyl or aryl selected from phenyl, naphthyl or indanyl, or aheterocycle selected from the group consisting of pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine,triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline,pyrazolidine, imidazolidine, piperidine, furan, pyran, isothiazole,isoxazole, and thiophene, wherein R₁ may be optionally interrupted byone or more heteroatoms or heterogroups; R₂ is a (C₁₋₆)alkyl orpolyfluoro(C₁₋₆)alkyl group; and the N→O derivatives of the compounds offormula I and the pharmaceutically acceptable salts thereof; providedthat when Y is methylene and R is hydrogen, R₁ is not hydrogen.
 2. Thecompound according to claim 1, wherein R is hydrogen, (C₄₋₇)cycloalkyl,aryl selected from phenyl, naphthyl or indanyl, (C₁₋₈)alkyl optionallybranched and/or substituted by (C₄₋₇)cycloalkyl or aryl selected fromphenyl, naphthyl or indanyl; R₁ is hydrogen, and W is a substitutedpyridine.
 3. A process for the preparation of a compound according toclaim 1 having the structure of a 3,4-dihydro-isoquinoline, comprising:reacting a compound of formula II:

wherein R, R₁, R₂ are each as defined in claim 1, with a compound offormula III: W—Y—Z  (III) wherein W and Y are each as defined in claim 1and Z is a carboxy group or a reactive derivative thereof, providedthat, when Z is a carboxy group, the reaction occurs in the presence ofan activating agent, to give a compound of formula IV:

wherein R₁, R₂, R, W and Y are each as defined in claim 1, which iscyclised.
 4. A pharmaceutical composition comprising a compoundaccording to claim 1 in admixture with a carrier.
 5. A pharmaceuticalcomposition according to claim 4 in a form suitable for parenteral,oral, transdermal, or inhalational administration.
 6. A pharmaceuticalcomposition according to claim 5 in the form of a liquid, tablet,capsule, or granulate.
 7. A method for inhibiting PDE4 comprisingadministering an amount of the compound of claim 1 effective to inhibitPDE4.
 8. A method for treating a disease or pathology involving PDE4 orTNFα, comprising administering an amount of the compound of claim 1effective to inhibit PDE4 or TNFα to a subject in need thereof.
 9. Themethod of claim 8, wherein said disease or pathology is an allergic orinflammatory disease.
 10. The method of claim 8, wherein said disease orpathology is a respiratory disease.
 11. The method of claim 8, whereinsaid disease or pathology is selected from the group consisting ofemphysema, chronic obstructive pulmonary disease (COPD), chronicbronchitis, asthma and allergic rhinitis.
 12. The compound of claim 1,wherein R is H.
 13. The compound of claim 1, wherein R₁ is H.
 14. Thecompound of claim 1, wherein R₂ is (C₁₋₆)alkyl.
 15. The compound ofclaim 1, wherein R₂ is polyfluoro (C₁₋₆)alkyl.
 16. The compound of claim1, wherein Y is methylene.
 17. The compound of claim 1, wherein Y isethylene.
 18. The compound of claim 1, wherein W is a heterocyclesubstituted by a halogen, (C₁₋₄)alkyl, hydroxy, nitro or carboxy. 19.The compound of claim 1, wherein W is pyridine which may be optionallysubstituted by a halogen, (C₁₋₄)alkyl, hydroxy, nitro or carboxy.